IRS-1-MEDIATED INHIBITION OF INSULIN-RECEPTOR TYROSINE KINASE-ACTIVITY IN TNF-ALPHA-INDUCED AND OBESITY-INDUCED INSULIN-RESISTANCE

Tumor necrosis factor-alpha (TNF-alpha) is an important mediator of in sulin resistance in obesity and diabetes through its ability to decrea se the tyrosine kinase activity of the insulin receptor (IR). Treatmen t of cultured murine adipocytes with TNF-alpha was shown to induce ser ine phosphorylation of insulin receptor substrate 1 (IRS-1) and conver t IRS-1 into an inhibitor of the IR tyrosine kinase activity in vitro. Myeloid 32D cells, which lack endogenous IRS-1, were resistant to TNF -alpha-mediated inhibition of IR signaling, whereas transfected 32D ce lls that express IRS-1 were very sensitive to this effect of TNF-alpha . An inhibitory form of IRS-1 was observed in muscle and fat tissues f rom obese rats. These results indicate that TNF-alpha induces insulin resistance through an unexpected action of IRS-1 to attenuate insulin receptor signaling.